Continuous monitoring of tumor hypoxia using near-infrared spectroscopy and tomography with a photonic mixer device

ABSTRACT

A device and a method to measure the concentrations of oxygenated and deoxygenated hemoglobin in tissue around a tumor via near-infrared (NIR) spectroscopy with a photonic mixer device (PMD) is described.

BACKGROUND

Technical Field

The present disclosure relates generally to continuous monitoring of theoxygenation of tissue, particularly tumor hypoxia, and moreparticularly, to a method and a device for calculating theconcentrations of oxygenated and deoxygenated hemoglobin in tissuesurrounding a tumor.

Background Description

The microenvironment around a solid tumor is generally hypoxic. Theratio of deoxygenated to oxygenated hemoglobin concentration in tissuesurrounding a tumor is higher than that in healthy tissue. By measuringtissue oxygenation, the functional behavior of a tumor may be assessed.Tissue oxygenation status may also be used to assess the effectivenessof conventional or neoadjuvant chemotherapies and to determine diseaseprogression and aid in prognosis.

Near-infrared (NIR) absorption spectroscopy is a technique that has beenused to measure the relative amounts of oxygenated and deoxygenatedhemoglobin in tissue. In the NIR spectral window of 600-1000 nm, photonpropagation in tissues is dominated by scattering rather thanabsorption. To make accurate measurements of hemoglobin concentration inthe target tissue, the absorbed and scattered fractions of photons haveto be decoupled. However, with continuous wave NIR absorptionspectroscopy, which employs steady-state illumination, it is usuallydifficult to separate the absorbed and scattered fractions of photons.Therefore, conventional methods of NIR absorption spectroscopy do notallow accurate measurements of oxygenated and deoxygenated hemoglobinconcentrations in tissue surrounding a tumor. To remedy this,researchers have developed various time- and frequency-domain techniquesto measure the scattered and absorbed fractions of photonsindependently, and thereby calculate more accurate values of absolutehemoglobin concentrations. These measurement techniques that allowabsorption and scattering to be measured separately are collectivelyreferred to as Diffuse Optical Spectroscopy (DOS). When the scatteredand absorbed fractions of photons are used for spatial reconstruction oftissue, the techniques are referred to as Diffuse Optical Tomography(DOT).

While there are commercially available continuous-wave NIR DOS devices(e.g. INVOS™ oximetry system from Medtronic-Covidien, NIRO-200NX NearInfrared Oxygenation Monitor from Hamamatsu, etc.), frequency domain NIRDOS devices have not transitioned from research to real-world use due toadded complexities of the frequency domain techniques. The frequencydomain DOS devices that are currently used for research are generallybulky and expensive, and therefore, cannot be easily translated intomedical equipment for use in real-world hospital settings or at thepoint-of-care.

Thus, there remains a need to develop miniaturized, low-cost frequencydomain spectroscopy and tomography devices that can be applied forcontinuous tissue oxygenation measurements.

SUMMARY

The present disclosure is directed to a device and a method formonitoring tumor hypoxia. The device and method of the presentdisclosure can be used for continuous monitoring of the functionalstatus of tumors in patients undergoing chemotherapy. The device can beminiaturized so that it can be either implanted into a patient's bodynear a tumor, or the device can be mounted on a patient's body near atumor site in the form of a wearable device. In some implementations,the device can be handheld such that it can be used at the point-of-care(e.g., at a patient's hospital bedside, in a physician's office, or at apatient's home) for evaluating the functional status of a tumor.

One aspect of the present disclosure is a device for continuousmonitoring of a tumor in a tissue region. The device can comprise a PMDcamera chip and at least one amplitude modulated near-infrared lightsource horizontally separated from the PMD camera chip, such that thePMD camera chip and the near-infrared light source are in a reflectiongeometry.

Another aspect of the present disclosure is a method for continuousmonitoring of tumor hypoxia. The method comprises: a) illuminating atissue region having a tumor with an amplitude modulated near-infraredlight source provided in close proximity to the tumor; b) recordinglight reflected from the tissue region using a multi-pixel PMD camerachip provided in close proximity to the tumor, wherein the near-infraredlight source is horizontally separated from the PMD camera chip; c)measuring amplitude and phase shift of the reflected light; d)calculating absorption and reduced scattering coefficients using theamplitude and phase shift of the reflected light; e) repeating steps a-dfor at least two different wavelengths of light; and f) calculating theconcentrations of oxygenated and deoxygenated hemoglobin in the tissueregion using the absorption and reduced scattering coefficientscalculated for the at least two different wavelengths of light.

Other embodiments of this disclosure are contained in the accompanyingdrawings, description, and claims. Thus, this summary is exemplary only,and is not to be considered restrictive.

BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate the disclosed embodiments andtogether with the description, serve to explain the principles of thevarious aspects of the disclosed embodiments. The accompanying drawingsare schematics and not necessarily drawn to scale. In the drawings:

FIG. 1 is a schematic side view of a NIR spectroscopic device, accordingto an exemplary embodiment;

FIG. 2 shows the time delay and phase shift of reflected light as aresult of a tumor in the sampled volume of a tissue region, according toan exemplary embodiment;

FIG. 3 is a schematic top view of a NIR spectroscopic device, accordingto an exemplary embodiment;

FIG. 4 is a chart showing phase shifts computed at different modulationfrequencies and at different source-detector separations, according toan exemplary embodiment; and

FIG. 5 is a schematic diagram of a NIR spectroscopic device, accordingto an exemplary embodiment.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the disclosed embodiments, as claimed.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made to certain embodiments consistent with thepresent disclosure, examples of which are illustrated in theaccompanying drawings. Wherever possible, the same reference numbers areused throughout the drawings to refer to the same or like parts.

The present disclosure describes a technique to measure the oxygenationstatus of tissue around a solid tumor via frequency domain NIRspectroscopy and tomography using a photonic mixer device (PMD). PMD isa semiconductor structure based on CCD- or CMOS-technology where eachpixel comprises two charge storage locations (i.e., sub-pixels).Photoelectrons in the PMD are assigned alternately to the two sub-pixelsas determined by a radiofrequency (RF) control voltage. The RF voltagesignal is phase locked to a scene-illuminating light source that ismodulated at the same frequency. The light reflected from the scenegenerates photoelectrons, which causes charge to build up at the twosub-pixels. The charge collected at the two sub-pixels gives thein-phase and 180° out-of-phase components of the reflected light signal.Using this information, the phase shift of the reflected light iscalculated using Equation (1) shown below.

$\begin{matrix}{{{Phase}\mspace{14mu}{Shift}} = {2\pi*\frac{V_{Q}}{\left( {V_{I} + V_{Q}} \right)}}} & (1)\end{matrix}$

where V_(I) and V_(Q)) are the in-phase and out-of-phase components ofthe reflected light signal. The phase shift can be used to estimate thedistance between the camera and the object that is being illuminated.When used for distance sensing, the PMD devices are often referred to astime-of-flight (ToF) cameras. In exemplary embodiments of the presentdisclosure, PMD-based ToF cameras can be used for measuring theamplitude and phase shift of reflected light signals, and the amplitudeand phase shift values can then be used for measuring optical propertiesof biological tissue (instead of distance from the object beingilluminated).

In exemplary embodiments, the amplitude and phase shift between thereflected and incident light can be used to measure tissue absorptionand reduced scattering coefficients (μa and μs′), which can then be usedto measure concentrations of oxygenated and deoxygenated hemoglobin.This is possible because absorption of light in tissue depends linearlyon the concentrations of tissue chromophores (i.e., oxygenatedhemoglobin, deoxygenated hemoglobin, water, lipids, etc.). Thewavelength-dependent absorption coefficient is given by Equation (2)shown below.μ_(a)(λ)=Σε_(i)(λ)C _(i)  (2)

Where ε_(i)(λ) is the wavelength-dependent extinction coefficient(usually known for typical tissue chromophores) and C_(i) is theconcentration of the ith chromophore. By measuring μ_(a) at multipleoptical wavelengths, a system of coupled equations (equation (2)) isformed, which can then be solved to yield the unknown chromophoreconcentrations. Generally, to estimate the concentrations of Nchromophores, one must determine μ_(a) at N or more wavelengths. Thus,in exemplary embodiments, to measure concentrations of oxygenated anddeoxygenated hemoglobin, μ_(a) at two or more wavelengths is determined.

FIG. 1 shows a side view of an exemplary PMD-based NIR spectroscopicdevice 10 that can be used for determining optical properties of abiological tissue 30. Device 10 comprises a NIR light source 20positioned in close proximity to a tumor site. In exemplary embodiments,NIR light source 20 can be a LED, fiber-couple laser, or a tunable laseremitting light at appropriate wavelengths. In exemplary embodiments, NIRlight source 20 can emit light at a wavelength of about 600 nm to about1000 nm. In some embodiments, two or more NIR light sources 20 can beused to emit light at different wavelengths. As previously discussed, tomeasure oxygenated and deoxygenated hemoglobin concentrations, phase andamplitude measurements at two wavelengths is required. Therefore, insome embodiments, two NIR light sources 20 can be used to emit light attwo different wavelengths. In another embodiment, multiple NIR lightsources 20 can be used to emit light of different wavelengths. Use ofmore wavelengths permits measurement redundancy, which in turn canimprove the accuracy of hemoglobin concentration measurements.

Determination of hemoglobin concentrations requires the separation oftissue absorption from tissue scattering at more than one opticalwavelength. In exemplary embodiments, wavelengths that minimizecross-talk between the oxygenated and deoxygenated hemoglobin can bechosen. For example, in some embodiments, at least one wavelength withinthe NIR window can be below the isosbestic point of hemoglobin (i.e.,800 nm) and one can be above this isosbestic point. For example, usingonly two wavelengths, a pair at about 780 nm and about 830 nm can beused. In some embodiments, a pair at about 660 nm and at about 940 nmcan be used for the phase and amplitude measurements.

In exemplary embodiments, NIR light source 20 can be amplitude modulatedat a frequency in the 10-1000 MHz range. For example, in someembodiments, NIR light source 20 can be amplitude modulated at 200 MHz.In another embodiment, NIR light sources can be amplitude modulated at30 MHz.

Referring again to FIG. 1, NIR spectroscopic device 10 comprises adetector 40 positioned in close proximity to the tumor site. Detector 40measures both phase and amplitude of the received modulated lightrelative to the incident light. In exemplary embodiments, device 10 canbe operated in reflectance mode, such that NIR light source 20 anddetector 40 are horizontally separated and positioned on the same sideof the tissue, as shown in FIG. 1. The light reflected from the tissueis captured by detector 40. The crescent shaped region, shown in FIG. 1,is the sampled volume in the reflection geometry. When operated intransmittance mode, NIR light source 20 and detector 40 can bepositioned on opposite sides of the tissue region, and light transmittedthrough the tissue is captured by detector 40. In the reflectiongeometry, light injected into the tissue from NIR light source 20 can bedetected at a distance p by detector 40. In exemplary embodiments, theseparation distance p between NIR light source 20 and detector 40 can beapproximately twice the depth of the tumor from the tissue surface.

In exemplary embodiments, detector 40 can be a PMD-based ToF camera. Insome embodiments, detector 40 can be a multi-pixel PMD camera chip. Insuch embodiments, the amplitude and phase shift information can berecorded at each pixel for different modulation frequencies of NIR lightsource 20 and detector 40. The amplitude and phase shift information canthen be used to estimate the real and imaginary parts of the complexwavevector (k) associated with the diffuse photon density waves in themedium. In an exemplary embodiment comprising an infinite, homogeneousturbid media, the fluence rate (U(r)) of the diffuse photon densitywaves can be written as:

$\begin{matrix}{{U(r)} = {\frac{\vartheta\; S_{ac}}{4\pi\;{Dr}}{\exp\left( {- {kr}} \right)}}} & (3)\end{matrix}$

The complex wavefactor k is defined as k=k_(r)+ik_(i) andk²=(−θμ_(a)+iw)/D, where θ is the speed of light in the medium, D is thephoton diffusion coefficient and D=θ/3(μ_(s)′+μ_(a)). The reflectanceamplitude at a distance r from the light source is equal to k_(r)*r,while the phase shift at a distance r from the light source is equal tok_(i)*r. From the complex wavevector (k), absorption coefficient μ_(a)and reduced scattering coefficient μ_(s)′ can be calculated usingequation (3).

In exemplary embodiments, the absorption and scattering coefficients(μ_(a) and μ_(s)′, respectively) recorded at multiple light wavelengthscan be used to calculate the concentrations of oxygenated anddeoxygenated hemoglobin. For example, in some embodiments, equation (2)can be used to calculate the hemoglobin or any other chromophoreconcentration.

FIG. 2 illustrates the effect of a tumor in the sampled volume of atissue region. Presence of a solid tumor can cause more light scatteringand delay in light reaching detector 40, which is turn can cause phaseshift between the incident and reflected light. The charge collected atthe two sub-pixels is shown as Q₁, Q′₁ and Q₂, Q′₂ in FIG. 2. The phaseshift is registered as an increase in charge (Q₂′) at the second chargestorage location (i.e., the out-of-phase pixel). The amount of phaseshift can be calculated from the charges collected at the two chargelocations. The amplitude and phase shift can be recorded at each pixelof PMD-based detector 40 for different modulation frequencies.

In exemplary embodiments comprising a multi-pixel PMD camera chip asdetector 40, coarse structural and positional information of the tumorcan also be determined by using tomographic reconstruction algorithm. Insome embodiments, multiple NIR light sources 20 can be arranged in anarray around the PMD-based detector 40, as shown in FIG. 3. In anotherembodiment, one or more NIR light sources 20 are mounted with a motor 70to move the light source around the PMD-based detector 40. In exemplaryembodiments, multiple NIR light sources 20 can be operated in amultiplexed fashion (either time division or frequency division) suchthat the amplitude and phase signal for each source is separatelyrecorded. The information recorded can then be used to tomographicallyreconstruct the spatial distribution of absorbers and scatterers withinthe tissue medium, thereby getting information on the size, structureand position of the tumor.

FIG. 5 shows a schematic diagram of a NIR spectroscopic device 10′,according to an exemplary embodiment. Due to the small form factors ofPMD ToF cameras, device 10′ can be implemented as a handheld device, awearable device, or an implantable device. Device 10′ can include aprocessor 50, a communication system 60, and a power system 80 inaddition to NIR light sources 20 and detector 40. Processor 50 cancontrol the overall operation of device 10′. Processor 50 can alsoprocess and/or analyze the recorded phase and amplitude data anddetermine an oxygenation status of the target tissue. Communicationsystem 60 can comprise wired or wireless communication capabilities,including antennas, transceivers, encoders, decoders, etc. In someembodiments, communication system 60 can transmit the processed data toa remote storage device 92 or a remote display device 94 where theoxygenation status can be displayed. In some embodiments, communicationsystem 60 can transmit raw data to a remote processing device 90 or acloud server 100 where calculations can be performed and the results canbe transmitted to the patient or a healthcare provider. In someembodiments, device 10′ can include on-chip electronics to pre-processthe recorded data prior to processing by processor 50, or prior totransmission to the remote processing device 90 or cloud server 100. Insuch embodiments, device 10′ can include amplifiers, analog-to-digitalconverters, multiplexers, and other electronic circuitry to pre-processthe acquired data. The power system 80 can power processing system 50,communication system 60, NIR light sources 20 and detector 40. In someembodiments, device 10′ can be wirelessly powered. In such embodiments,power system 80 can include a supercapacitor, a battery, or some othertype of charging system that can be charged wirelessly by a remotedevice 110. In some embodiments, optical powering using an array ofphotovoltaic cells can be used to power the embedded electronics ofdevice 10′ or recharge its battery.

Example: Application of PMD-ToF Camera for Phase Shift Measurements

Phase shift between incident and reflected light was computed for manydifferent modulation frequencies in a semi-infinite medium (with opticalproperties similar to tissue) in order to verify that representativephase shifts are measurable using a PMD ToF camera. FIG. 4 shows thephase shifts for different modulation frequencies (f) at differentsource-detector separations p. The results indicate that assource-detector separation increases, the phase shift increase. As anexample, when ρ=5 cm and f=30 MHZ, the phase shift is 35°, whichcorresponds to a time delay of ˜3 ns. When used for distance sensing,time delay of ˜3 ns corresponds to a camera-to-object distance of 45 cm,which can be detected by a PMD ToF camera, thus implying that acorresponding phase shift of 35° can also be detected by a PMD ToFcamera.

The foregoing description has been presented for purposes ofillustration. It is not exhaustive and is not limited to the preciseforms or embodiments disclosed. Modifications and adaptations will beapparent to those skilled in the art from consideration of thespecification and practice of the disclosed embodiment. Moreover, whileillustrative embodiments have been described herein, the disclosureincludes the scope of any and all embodiments having equivalentelements, modifications, omissions, combinations (e.g., of aspectsacross various embodiments), adaptations and/or alterations as would beappreciated by those skilled in the art based on the present disclosure.The limitations in the claims are to be interpreted broadly based on thelanguage employed in the claims and not limited to examples described inthe present specification or during the prosecution of the application.The examples are to be construed as non-exclusive. Furthermore, thesteps of the disclosed methods can be modified in any manner, includingby reordering steps and/or inserting or deleting steps. It is intended,therefore, that the specification and examples be considered asillustrative only, with a true scope and spirit being indicated by thefollowing claims and their full scope of equivalents.

The invention claimed is:
 1. A device for continuous monitoring of atumor in a tissue region, the device comprising: a PMD camera chip; andat least two amplitude modulated near-infrared light sourceshorizontally separated from the PMD camera chip such that the PMD camerachip and the at least two near-infrared light sources are in areflection geometry, wherein a first amplitude modulated near-infraredlight source emits near-infrared light at a first wavelength, the firstwavelength below an isosbestic point of hemoglobin, and wherein a secondamplitude modulated near-infrared light source emits near-infrared lightat a second wavelength, the second wavelength above the isosbestic pointof hemoglobin.
 2. The device of claim 1, wherein the PMD camera chip isa multi-pixel PMD camera chip.
 3. The device of claim 1, wherein the atleast two modulated near-infrared light sources are included in an arrayof modulated near-infrared light sources arranged around the PMD camerachip.
 4. The device of claim 1, wherein each of the at least twomodulated near-infrared light sources is modulated at differentfrequencies.
 5. The device of claim 1, further comprising a motor tomove the at least two modulated near-infrared light sources around thePMD camera chip.
 6. The device of claim 1, further comprising a wirelesscommunication system to transmit recorded data to a remote processingunit or a cloud server.
 7. The device of claim 1, further comprising awireless power system.
 8. The device of claim 1, wherein a distancebetween the modulated near-infrared light sources and the PMD camerachip is approximately twice the depth of the tumor from the surface ofthe tissue region.